The Impact of Aging and Ovariectomy on Cardiac Contractile Function in Isolated Ventricular Myocytes

Abstract

Previous studies have shown that cardiac contractile function declines with age in ventricular myocytes from 24 month old males but not females. As estrogen modulates cardiac contractile function, age-dependent changes in estrogen may help preserve contraction in the aging female heart. The present study examined the effects of extreme old age as well as short and long term estrogen deprivation on cardiac contractile function. Cardiomyocytes were isolated from young adult (~7 mos) and senescent (~32 mos) C57BL/6 male and female mice, or from young adult (~8 mos) and aged (~24 mos) ovariectomized or sham control female mice. Myocytes were loaded with Fura-2 and paced at 2 Hz (37°C). Results showed that while Ca2+ dysregulation occurred in both senescent male and female mice, contractile function was preserved in female myocytes, even with extreme old age. This suggests that while aging causes Ca2+ dysregulation in males and females, contractile function is preserved in females. In other experiments, the effect of short ovariectomy on the excitation-contraction (EC) coupling pathway was investigated. Short term ovariectomy enhanced sarcoplasmic reticulum (SR) Ca2+ storage and release, by augmenting SR Ca2+ content and by increasing Ca2+ transients, Ca2+ sparks and EC-coupling gain. These findings suggest that estrogen may play a role in limiting SR Ca2+ loading and Ca2+ release in the female heart. The present study also investigated the effect of long term ovariectomy on the aging female heart. The results showed that long term ovariectomy enhanced Ca2+ influx and increased SR Ca2+ storage and release, but did not affect contractile function. This was due to a decrease in myofilament Ca2+ sensitivity with long term ovariectomy. However, enhanced Ca2+ levels did lead to larger spontaneous Ca2+ transients and greater abnormal electrical activity in the form of early afterdepolarizations. Together, the results suggest that aging as well as short and long term estrogen deprivation leads to Ca2+ dysregulation and spontaneous SR Ca2+ release. In the aging female heart, this Ca2+ dysregulation may increase the susceptibility to cardiovascular disease and dysfunction.